Alkylation of malonic esters



United States Patent 2,894,981 A LKYLATION OF MALON'IC ESTERS Bianka Tchoubar, Paris, France, assignor to Centre National de'la Recherche Scientifique, Paris, France, a corporation of France Application December 18, 1953 Serial No. 399,150

Claims priority, application France May22, 19'50 1' Claim. (Cl. 260-485) No Drawing.

inwhich the hydrocarbon radical: RR"HC- is an alkyl group branched at a which may be designated more generally by R; R and R" are themselves alkyl groups each having at least one carbon atom. Thus whenR and'R" both correspond to the group CH R represents the isopropyl group: (CHghHC-g R represents a hydro carbon radical, saturated or not, and'comprising a number of carbon atoms generally less than 6.

Now, my invention concerns a process for the alkylation of monoalkylated malonic esters in case'one of the substituent alkyl groups is a hydrocarbon radical of the R type and the other substituent is of the R' type whatever may be the order in which the substituents are introduced into the malonic'ester. My invention concerns more especially a special alkylation' agent making it possible to obtain easily and'with a goodyield the second alkylation of the malonic ester when the normal alkylation is diflicult.

It is known that the conventional alkylationmethod generally used for effecting the substitution of a hydro carbon radical for a hydrogen atom of an unsubstituted malonic ester consists in reacting an alkyl halide with a malonic ester, in the presence of a sodating and alkylating agent and of a solvent, the solvent being methanol or ethanol and the condensing agent being the corresponding sodium alcoholate. But if this method gives good results each' time a mono-substituted malonic ester is to be prepared, things are different when it is desired to introduce a .second sub'stituentalkylgroup in to the malonic ester, particularly when one of the two substituents ofiers a branched structure of the Rtype.

In the latter case, and particularly when R and R together, make a total ofat'least four carbon atoms, the yield of the dialkylation' by the conventional method drops very low, below 10%, often near 5%; the operation then becomes very costly forindustrial exploitation. These difiiculties have been known for a long time (Fischer and Dil'they, Ann. 335, 1904, p. 337; V. H.

ice

Wallingford, A. Thorpe, A. M. Homeyer, J. Am. Soc. 1942, 64 p. 580; Shonle, Keltchand Swan son, J. Am. Chem. Soc. 1930, 5 2; p; 2440). These authors reported that the preparation of disubstituted malonic esters comprising a substituent branched at a of the R type, is very diflicult and even, in some cases, impossible by the conventional method.

This difficulty is explained by the very procedure of the'reaction the latter being very sensitive to steric hind'rance. It so happens that the-alkyl group's comprising a branching at or are very bulky when a malonic ester has to be alkylated, the structure and constitution of which are already such as-to determine a certain'inertia of the alkylation reaction. It is known, indeed,.that the replacement reaction for each one of the two hydrogen atoms for instance of ethyl malonate, by R andR hydrocarbon radicals by means of the corresponding halogen'ated derivatives, is effected in two steps. The first step (I) consists in" the sodation of the malonic ester by sodium ethylate; the second step (11-) consists in replacing sodium by the R or R radicals supplied by the corresponding halog'enated derivative or X X being a halogen atom; The two following equations arera schematic showing this double reaction:

n ooo'ozn,

the step (I) is anequilibrium reaction; It will be realized, therefore, that'wh'en the alkylation is eflected using sodium ethylate as a sodation agent, there is always present a certain amount of sodium ethylate which with XR (or XR'") causes a production in variable proportions, of a secondary reaction (llDleading to'an etheroxide:

This secondary reaction is of very little importance, in the case of the replacing of the first hydrogen atom of'the ethyl malonate but itmay' become very important when replacing by an alkyl group the second hydrogen of the mono-substituted malonate In particular, and as already noted above, it is in case oneof-the two substituen'ts is R' and the other one R, i.e., R'-RHC, that the secondary reaction III beeomes very important, so that the formation of ethyl dialkylmalonate takes place with a very poor' yield. This is due to the steric hindrance presented by' thehydrocarbon radical R, causing a considerable slowing down of the substitution reaction II of sodium fixed on the mono-substituted ethylmalonate.

The main reaction II is then much' slower than the re- I action IIIleading-to the ether-oxide, which c'au'sesthe evolution of the phenomenon in'iavour of the'latter'. The order in which the radicals R and R' are intro duced-into the malonic ester is of little importance.

It should be noted that the inertia of the reaotioii II decreases considerably if, instead of a radical R, branched on the carbon atom at, one has to deal with a hydrocarhon radical which carries the branching at 8, 'y, w. In such cases, the steric hindrance is no longer felt and it is not necessary to use special conditions such as those taught by my invention for obtaining results.

It appears clearly from the above, that the conventional method involves unquestionable deficiencies each time the dialkylation of a malonic ester involves the use of a R substituent branched at on.

However, this latter method is commended through the U.S.A. Patent No. 1,985,217 to Eli Lilly (1934). Now, despite the fact that it does not appear in said patent the yields which are obtained when strictly following the working method described in this patent do not exceed 10%, often about about 5% for the ethyl (ethyLI-butyDdi-ethyl malonate, the main product of the reaction being formed of an ether-oxide resulting from the action of bromo-3-hexane on sodium ethylate: C3H7CHC1H5+N8.003H5 C3H7-CHC2H5+N&BP

Various authors have studied as seen above, for mentioning the poor conditions of reaction II, but also for endeavouring to supply a better solution. Thus Wallingford, Melvin and Thorpe (1M. Chem. Soc. 1942, 64, p. 580) tried to avoid the difiiculty by eliminating the alcohol after sedation I of the mono-substituted malonate by sodium ethylate. This elimination which is effected by distillation or by driving off by means of other solvents such as an alkyl carbonate for instance, is difiicult and time consuming,

particularly if it is desired to eliminate all traces of ethanol.

On the other hand, it is known by W. B. Renfrow, J. Am. Chem. Soc. 681301, 1946 that for carrying out alkylation of B-ketoesters, methylic and ethylic alcohols are advantageously replaced by tertiary butylic alcohol. However, in this case the use of this solvent is not imparted by consideration of sterical nature.

I have now found a very simple and efficient solution relating to the o'btention of esters of substituted malonic acid comprising an alkyl group R branched at c: and an alkyl group of the R" type. In accordance with my invention the method for effecting the di-substitution of malonic ester with a very good yield consists in using sodium tertiary butylate in tertiary butylic alcohol medium as condensing agent for a mono-substituted malonic ester. The use of this reagent makes it possible to prepare with yields comprised between 60 and 80%, without any difliculty, di-substituted ethyl malonates, comprising an R radical ramified at The following table" gives, by way of example, an outline of the main -di-substituted malonates corresponding to the general formula R O O O C3115 EU (a) CO OCzHB in which the hydrocarbon radical: R HC is an alkyl group branched at a which may be designated more generally by R; R and R are themselves alkyl groups each having at least one carbon atom and R represents a hydrocarbon radical, saturated or not, and comprising a number of carbon atoms generally less than 6, which have been easily prepared according to my in vention. Diethylic ester of malonic acid was taken as a base of the transformation and the nature of R, i.e. of R and R", and of R has been varied. The fourth column shows the pure products yields obtained and the fifth column the physical constant concerning the boiling point. It can be seen that the yields are generally very high. I

the problem, not only, i

TABLE R R" R'" Yield, E. P., 0.

Percent CH3 CH3 OzHs 65 112-115/18 mm. of Hg.

CH3 CH3 04119 60 130-131/20 mm. of Hg.

OH; CzHs GaH7 70 135-136/20 mm. of Hg.

CH; O3H1 H3 78 135-137/20 mm. of Hg.

CH3 C3117 02115 75 139-142/20 mm. 0f Hg.

CH3 CaH1 CsH7 72 146l47/20 mm. of Hg.

0H3 04H GHQ 75 130-132/10 mm. of Hg.

a C4He 03111 72 145-146/12 mm. of Hg.

CH3 C5Hn CzHs 85 141-143/14 mm. of Hg.

Allyl 65 129-130/12 mm. of Hg. (J2EE 73 125-127/11 mm. of Hg. 02H} C3H7 CH3 62 130-131/11 D1111. of Hg.

CZHs 03H1 C2115 75-80 144-145/18 mm. of Hg.

OzHs 03H; 04119 68 160-162/28 mm. of Hg.

C2Hs C4111; OaHs 60 146-148/14 mm. of Hg.

02115 051111 02115 70 152-153/16 mm. of Hg.

aH1 03H? CH3 65 137-139/15 mm. of Hg.

C3H7 CsH-z CzHr 58 141-144/15 mm. of Hg.

03H1 C4111; OzHs 63 157158/16 mm. of Hg.

The following numerical example will serve for illustrating the working method according to which each one in the diethylic esters of the disubstituted malonic acid indicated in the foregoing table has been prepared. This working method is substantially the same for all products, only the proportions of the used reagents may vary, which is easy to calculate by the man skilled in the art.

Preparation of ethyl (elhyl-l-bufyDethyl malonme To sodium tertiary butylate prepared by the action of one mole (23 g.) of sodium on 800 cc. of dry tertiary rbutylic alcohol, there was added 1 mole of (etl1yl-' 1-butyl) di-ethyl malonate. To the solution thus obtained, there was added, while stirring, 1.2 moles of ethyl bromide heated to reflux, while stirring was effected. After heating for 7 to 8 hours and after treating in the usual manner (elimination of the tertiary butylic alcohol, dissolving the residue in water, other extraction, evaporation of the solvent and fractioning in vacuum of the resultant product) there was obtained the ethyl (ethyl-l-butyl) malonate with a yield of 75 to 80%. Boiling point 144-145" C./18 min/Hg. n :1.4375-1.438O.

From the disubstituted alkyl malonates obtained according to the method of my invention, all sorts of products can be prepared obviously, particularly the corresponding barbituric and thio-barbituric acids.

In the above description and examples, reference has been made to ethylic esters of disubstituted malonic acid. Now, it may be easily understood that my invention includes dialkylation both of methylic or ethylic ester or of higher alkyl esters of the malonic acid.

What I claim is:

An improved method for the production of diethyl (1-ethyl butyl) ethyl malonate consisting in heating under reflux diethyl (l-ethyl butyl) malonate with ethyl bromide in solution in dry tertiary 'butylic alcohol as a solvent and in the presence of sodium tertiary butylate as a condensing agent.

References Cited in the file of this patent UNITED STATES PATENTS FOREIGN PATENTS Germany Great Britain Mar. 25, 1930 Jan. 31, 1951 

